What is the preferred opioid, morphine or hydromorphone, for a patient with liver (hepatic) failure?

From the Guidelines

Hydromorphone is generally a better narcotic choice for patients with liver failure compared to morphine. Hydromorphone undergoes less hepatic metabolism and produces fewer active metabolites that could accumulate in liver dysfunction, as noted in the 2022 study 1. Morphine is extensively metabolized in the liver to morphine-3-glucuronide and morphine-6-glucuronide, which can accumulate in liver failure and potentially cause toxicity or prolonged effects.

When administering hydromorphone to patients with liver failure, it is recommended to start with lower doses (approximately 25-50% of the normal starting dose) and extend the dosing interval, as suggested by the principles of opioid use in patients with liver dysfunction 1. Close monitoring for signs of oversedation, respiratory depression, and other opioid-related side effects is essential. Dose titration should be done more cautiously than in patients with normal liver function.

Some key considerations for opioid use in patients with liver failure include:

• Using opioids cautiously in patients with end-stage liver disease
• Considering longer dosing intervals due to reduced opioid clearance
• Avoiding certain opioids, such as codeine and morphine, which are not recommended in liver failure
• Being aware of the potential for neuroexcitatory effects, such as myoclonus, especially with chronic opioid use or in patients with renal failure, electrolyte disturbances, and dehydration 1.

While hydromorphone is preferred, all opioids should be used carefully in liver failure, with frequent reassessment of pain control and side effects to guide appropriate dosing adjustments. The EASL recommendation to use paracetamol, morphine, and hydromorphone for pain control, while avoiding NSAIDs, tramadol, codeine, and oxycodone in patients with end-stage liver disease, also supports the use of hydromorphone in this context 1.

From the FDA Drug Label

1. 6 Hepatic Impairment The pharmacokinetics of hydromorphone are affected by hepatic impairment. Due to increased exposure of hydromorphone, patients with moderate hepatic impairment should be started at one fourth to one half the recommended starting dose depending on the degree of hepatic dysfunction and closely monitored during dose titration

The FDA drug label does not provide a direct comparison between morphine and hydromorphone in patients with liver failure. However, it does provide guidance on the use of hydromorphone in patients with hepatic impairment, recommending a reduced starting dose and close monitoring. No conclusion can be drawn about which narcotic is better to use in patients with liver failure based on the provided information 2.

From the Research

Comparison of Morphine and Hydromorphone in Liver Failure

• Morphine is metabolized by glucuronidation, and its clearance is decreased in liver failure, leading to an increased risk of accumulation and toxicity 3, 4.
• Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), which can cause neuroexcitatory phenomena with accumulation, particularly in patients with renal insufficiency 5, 6.
• In patients with liver disease, the administration of opioid analgesics, including morphine and hydromorphone, should be observed accurately, with lower doses administered at regular intervals based on signs of drug accumulation 7.

Pharmacokinetics and Pharmacodynamics

• The liver is the major site for biotransformation of most opioids, including hydromorphone, and liver disease can affect the pharmacokinetics of these drugs 3, 4.
• The clearance of morphine is reduced in liver failure, and its oral bioavailability is increased due to reduced first-pass metabolism 3.
• Hydromorphone has a higher risk of neuroexcitatory effects, including tremor, myoclonus, agitation, and cognitive dysfunction, particularly with increasing dose or duration of administration 5.

Clinical Considerations

• In patients with liver failure, the use of morphine is not recommended due to the risk of accumulation and toxicity 4.
• Hydromorphone may be a safer alternative to morphine in patients with liver failure, but its use should be carefully monitored due to the risk of neuroexcitatory effects 5, 6.
• The initial dose of opioids should be decreased, and the intervals between doses should be increased in patients with hepatic insufficiency to minimize the risk of adverse reactions 7.